2. Academic Validation
  3. Cancer-associated fibroblast-derived GAS6 increases resistance to chemotherapy through AXL/STAT3/ABCG1 in gastric cancer

Cancer-associated fibroblast-derived GAS6 increases resistance to chemotherapy through AXL/STAT3/ABCG1 in gastric cancer

  • Br J Cancer. 2026 Jan;134(1):72-84. doi: 10.1038/s41416-025-03218-8.
Tae Hoon Kim # 1 2 3 4,  Dagyeong Lee # 1 5,  Hye Jeong Oh 1,  In-Hye Ham 1 5,  Tuyen Thanh Tran 1,  Yulim Lee 1 2,  Tae-Min Kim 6 7 8,  Rolf A Brekken 9,  Zhang Zhang 10,  Ding Ke 10,  Hoon Hur 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea.
  • 2 Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea.
  • 3 Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon, Republic of Korea.
  • 4 Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea.
  • 5 Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon, Republic of Korea.
  • 6 Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
  • 7 Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
  • 8 CMC institute for Basic Medical Science, The Catholic Medical Center of The Catholic University of Korea, Korea, Republic of Korea.
  • 9 Hamon Center of Therapeutic Oncology Research and Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 10 School of Pharmacy, Jinan University, Guangzhou, China.
  • 11 Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea. [email protected].
  • 12 Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea. [email protected].
  • 13 Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon, Republic of Korea. [email protected].
  • 14 BK21 R&E Initiative for Advanced Precision Medicine, Ajou University School of Medicine, Suwon, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 41152601 DOI: 10.1038/s41416-025-03218-8
Abstract

Background: Chemoresistance induced by cancer-associated fibroblasts (CAFs) is well recognized, yet its mechanisms remain unclear and no CAF-targeted therapies are available. Gastric Cancer (GC) with extensive CAF infiltration correlates with poor prognosis, and emerging evidence highlights the GAS6/Axl axis in CAF-GC interactions. This study targets GAS6/Axl axis to overcome CAF-mediated chemoresistance and enhance chemotherapy efficacy.

Methods: We investigated the effect of 9im, a selective Axl Inhibitor, on CAF-induced chemoresistance in GC using transwell migration, western blotting, viability assays, flow cytometry, drug efflux assays and in vivo experiments. Transcriptome analysis identified chemoresistance-related genes, and luciferase assays assessed STAT3 binding to the ABCG1 promoter. RNA-ISH analyzed GAS6 + CAFs in GC samples, while public data evaluated the prognostic significance of ABCG1 and CAF markers.

Results: GAS6 expression was elevated in CAF. CAF-derived GAS6 promoted GC cell migration and chemoresistance via Axl activation, effects reversed by 9im. STAT3 bound to the ABCG1 promoter, enhancing expression, while STAT3 inhibition reduced ABCG1 levels. 9im restored chemosensitivity in GC models. Clinically, ABCG1 and CAF marker co-expression correlated with poor prognosis.

Conclusions: CAF-derived GAS6 induces GC chemoresistance via the Axl/STAT3/ABCG1 pathway. 9im restores chemosensitivity by inhibiting Axl and ABCG1-mediated efflux. Axl inhibitors with chemotherapy may improve GC treatment.

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